Complement can be produced locally or systemically and is a major link between infection and local or systemic inflammatory diseases, such as periodontitis or sepsis, respectively. However, little is known about local mechanisms that disrupt mucosal tissue-microbe homeostasis and set the stage for unwarranted complement activation. In this regard, periodontitis represents an attractive study model, as it is readily accessible for obtaining both microbial and host tissue samples to longitudinally investigate local inflammatory mechanisms. This highly prevalent disease (>47% of US adults) is initiated by a dysbiotic microbiota, leads to inflammatory destruction of tooth-supporting bone, and adversely affects systemic health in its severe form (8.5% of US adults). Periodontitis therefore urgently requires innovative treatments. The overarching concept in Project 3 of this POl is that complement is crucially and centrally involved in the initiation and amplification of destructive local inflammation in periodontitis through cross-talk interactions with the microbiota and other inflammatory pathways; hence, it represents a prime target for therapeutic intervention. Experiments have been designed to dissect the mechanisms of complement involvement in local tissue regulation of interieukin-17, a key cytokine produced by innate and adaptive immune cells and mediating inflammation and bone loss in periodontitis (Aim 1). On the basis of preliminary studies and those to be performed in Aim 1, appropriate complement inhibitors (Core B & Project 1) will be tested for their efficacy in treating periodontal inflammation and bone loss in non-human primates (Aim 2), a disease that shares key clinical and immunohistological features with human periodontitis. Local inflammation in this model will be investigated at the clinical, histological, and cellular/molecular level in a longitudinal approach that will also include periodic sampling of the periodontal biofilm to monitor complement-dependent dysbiosis. The C5a receptor (C5aR), a crucial target of microbial immune subversion leading to dysbiosis, and C3, required for the amplification of inflammation by the dysbiotic microbiota, will serve as initial targets of therapeutic intervention. Moreover, using a panel of pathway-specific inhibitors, we will dissect the initiation mechanism(s) leading to C3 activation and other complement pathways that may contribute to disease pathogenesis. Complement-specific drugs have already undergone successful safety trials, and promising interventions established in this project have potential for rapid translation to the clinic. Our longterm objective is to apply the mechanistic insights gained from studying local complement inflammation to the treatment of local infection-driven inflammatory diseases.